An inter-species platform for the study of the roles of the antioxidant response pathway in thyroid pathophysiology

ULB main applicant

Dr Sabine Costagliola, Faculty of Medicine

UNIL main applicant

Dr Gerasimos Sykiotis, Faculty of Biology and Medicine

Field

Medicine

Activity

Joint research project

Description

A new collaborative research project between the lab of Dr Sykotis and the lab of Dr Costagliola is proposed.

The Sykiotis lab has been studying the roles of the antioxidant response pathway in the thyroid gland in health and disease. Using mice and traditional 2D cell cultures, new factors have been identified that mediate responses of thyroid cells to various forms of stress encountered both during normal physiology of the thyroid gland and also during extreme conditions associated with thyroid disorders. These findings are completely original and very innovative because they address the long-standing questions of how oxidation is coupled to the metabolism of iodine, and how the protective mechanisms of thyrocytes against oxidative stress are linked to protective mechanisms against iodine overload. Nevertheless, certain aspects cannot be fully resolved with the aforementioned experimental models; specifically, differences in iodine organification cannot be modelled in 2D cell cultures, because it requires the 3D structure of the normal anatomical units of the thyroids, the sphere-shaped follicles. In addition, the developmental roles and the evolutionary conservation of the antioxidant response pathway in the thyroid remain unknown.

These issues can be addressed very efficiently via two ground-breaking models developed in the Costagliola lab. One is a method for in vitro differentiation of thyrocytes and 3D culture of follicles starting from mouse embryonic stem cells. The other is the use of a new zebrafish model to investigate in vivo thyroid development in a non-invasive manner.

In this context, we have outlined a project with the overall goal to combine the respective strengths and expertise of the two labs to elucidate the physiological and developmental functions and evolutionary aspects of the stress response pathway in the thyroid. The specific aims are the following:

To transfer to the Sykiotis lab the 3D follicle model established by the Costagliola lab in order to perform cell-based studies on the role of stress response pathways on iodine metabolism.

To transfer to the Costagliola lab expertise on the Nrf1 and Nrf2 pathways and their manipulation with pharmacological compounds.

To investigate in parallel the functions of these pathways in mice and in zebrafish using genetic means.

There is also added value beyond the specific research project: At ULB, and in Belgium more broadly, there is a vibrant thyroid research community. The Sykiotis group will thus come into contact with a broader network of thyroidologists, which will have a lasting structural effect on both partners, leading to new collaborations, both research and clinical. Conversely, UNIL is currently in the process of establishing a zebrafish platform, for which Dr Costagliola could be a precious advisor and a model for successful implementation of this versatile system.

Timeline

Autumn 2017: Visits of UNIL researchers to ULB

Autumn 2017 to summer 2018: Implementation of the 3D model at UNIL and implementation of the zebrafish model at ULB